While there is overwhelming evidence that reduced insulin/insulin like growth factor-1 (IGF1) signaling (IIS) extends lifespan in invertebrate and murine models, the impact of this evolutionarily conserved pathway on human longevity remains unclear. Research in the Suh lab has led to the discovery of two centenarian- enriched missense mutations in the IGF-1 receptor gene (IGF1R), A37T (M1) and R407H (M2), associated with decreased IIS in lymphocytes established from carriers as compared to non-carriers (Suh et al., PNAS, 2008). The M1 and M2 variants were shown to cause attenuation of IGF1 signaling, reduced expression of IGF1-activated genes, and delayed cell cycle progression relative to wild-type human IGF1R when expressed in Igf1r null mouse embryonic fibroblasts (Tazearslan et al., Aging Cell, 2011). While the association of IIS with longevity is known, the specific role of IIS in regulating human lifespan, including how missense mutations in IIS components modify survival and disease risk, is not known. The goal of this proposal is to elucidate the molecular and physiological mechanisms of longevity promotion by missense mutations in the IGF-1 receptor using cells expressing centenarian enriched variant receptor and mice carrying a knock-in of a centenarian associated variant. The IGF-1 receptor has been studied in mice in respect to aging but only in the context of knockout, or heterozygous deficiency. The IGF-1 receptor has multiple roles in regulating cellular and organism physiology including non-receptor functions and modification of other membrane bound receptors through dimerization. In addition, stimulation of the IGF-1 receptor activates multiple distinct intracelluar signaling cascades through specific ligand-receptor interactions and our preliminary data shows that centenarian associated mutations in IGF-1 receptor differentially affect these downstream signaling pathways in a tissue specific manner. In order to address this goal we will (1) examine IGF1R variant processing, assembly, protein-protein interaction, and impact on signaling in cell based assays; (2) define the effects of a centenarian associated IGF1R variant on growth, metabolism, and in vivo insulin/IGF-1 signaling in mice using the knock-in model we have produced; (3) determine the impact of the centenarian associated IGF1R variant on the response to high- fat diet, a model for age-related metabolic disease. We hypothesize that centenarian associated IGF1R variants have functionally relevant effects on cellular and organism physiology resulting from changes to protein function. We further hypothesize that these effects will be partly functionally distinct from simply reducing levels of IGF-1 receptor, including differential effects on downstream signaling and non-receptor functions of IGF1R. Lastly, we predict that these molecular changes and cellular effects will lead to beneficial systemic functional changes in the mouse knock-in model that underlie the association to human longevity, including resistance to metabolic stress in the high-fat diet paradigm. Understanding the physiological role of naturally occurring centenarian associated IGF1R genetic variation will pave the way for future development of therapeutic strategies for preventing and treating age-related disease based on the molecular mechanisms we describe.